The purpose of this study is to describe the epidemiology of pulmonary hypertension in individuals with HIV infection and to investigate its pathogenesis. Our preliminary data suggest that the prevalence of pre- clinical pulmonary hypertension in individuals with HIV infection is much higher than previously reported and is independently associated with HIV infection. However, very little is known about the progression of sub- clinical pulmonary hypertension, the natural history of elevated pulmonary arterial pressure (PAP) in HIV- infected individuals, or the pathogenesis of HIV-associated pulmonary hypertension. We propose to conduct a prospective observational cohort study to describe the natural history of pre- clinical pulmonary hypertension in patients with HIV and to determine the association between detectable viremia and injection drug use in the development and progression of pulmonary hypertension (Aim 1). In addition, we will investigate the mechanistic role of the HIV-1 Nef protein and HHV-8 infection in the development and progression of pulmonary hypertension in individuals with HIV (Aim 2). We will also compare endothelial function in HIV-infected patients with and without pulmonary hypertension (Aim 3). Strengths of this application include (1) having already identified HIV patients with elevated PAP to enroll into the study (2) the ability to rapidly recruit subjects from already existing cohorts of HIV-infected subjects (3) the full support of the Cardiology Division and the HIV/AIDS Division at San Francisco General Hospital;and (4) the collaboration of senior investigators at the University of Colorado and The Wistar Institute, Philadelphia, PA. In addition, the clinical databases, serum and plasma banks, and echocardiographic and hemodynamic data collected in this study will provide the basis for future collaborative efforts to better understand the natural history, etiology, pathogenesis, and treatment of pulmonary hypertension in individuals with HIV infection. Public health relevance: This study will potentially identify patients at risk for clinical pulmonary hypertension and allow clinicians to intervene with therapy beforehand. In addition, understanding more about the cofactors and pathophysiology behind HIV-associated pulmonary hypertension may lead to the development of new therapies in the future.